Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease
Abstract Caspases are critical regulators of cell death, development, innate immunity, host defense, and disease. Upon detection of pathogens, damage-associated molecular patterns, cytokines, or other homeostatic disruptions, innate immune sensors, such as NLRs, activate caspases to initiate distinc...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-05-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-025-00791-3 |
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| author | Eswar Kumar Nadendla Rebecca E. Tweedell Gary Kasof Thirumala-Devi Kanneganti |
| author_facet | Eswar Kumar Nadendla Rebecca E. Tweedell Gary Kasof Thirumala-Devi Kanneganti |
| author_sort | Eswar Kumar Nadendla |
| collection | DOAJ |
| description | Abstract Caspases are critical regulators of cell death, development, innate immunity, host defense, and disease. Upon detection of pathogens, damage-associated molecular patterns, cytokines, or other homeostatic disruptions, innate immune sensors, such as NLRs, activate caspases to initiate distinct regulated cell death pathways, including non-lytic (apoptosis) and innate immune lytic (pyroptosis and PANoptosis) pathways. These cell death pathways are driven by specific caspases and distinguished by their unique molecular mechanisms, supramolecular complexes, and enzymatic properties. Traditionally, caspases are classified as either apoptotic (caspase-2, -3, -6, -7, -8, -9, and -10) or inflammatory (caspase-1, -4, -5, and -11). However, extensive data from the past decades have shown that apoptotic caspases can also drive lytic inflammatory cell death downstream of innate immune sensing and inflammatory responses, such as in the case of caspase-3, -6, -7, and -8. Therefore, more inclusive classification systems based on function, substrate specificity, or the presence of pro-domains have been proposed to better reflect the multifaceted roles of caspases. In this review, we categorize caspases into CARD-, DED-, and short/no pro-domain-containing groups and examine their critical functions in innate immunity and cell death, along with their structural and molecular mechanisms, including active site/exosite properties and substrates. Additionally, we highlight the emerging roles of caspases in cellular homeostasis and therapeutic targeting. Given the clinical relevance of caspases across multiple diseases, improved understanding of these proteins and their structure–function relationships is critical for developing effective treatment strategies. |
| format | Article |
| id | doaj-art-9cf667f88e2546c7a906ea34da9bd69c |
| institution | Kabale University |
| issn | 2056-5968 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-9cf667f88e2546c7a906ea34da9bd69c2025-08-20T03:53:08ZengNature Publishing GroupCell Discovery2056-59682025-05-0111111810.1038/s41421-025-00791-3Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and diseaseEswar Kumar Nadendla0Rebecca E. Tweedell1Gary Kasof2Thirumala-Devi Kanneganti3Department of Immunology, St. Jude Children’s Research HospitalDepartment of Immunology, St. Jude Children’s Research HospitalCell Signaling TechnologyDepartment of Immunology, St. Jude Children’s Research HospitalAbstract Caspases are critical regulators of cell death, development, innate immunity, host defense, and disease. Upon detection of pathogens, damage-associated molecular patterns, cytokines, or other homeostatic disruptions, innate immune sensors, such as NLRs, activate caspases to initiate distinct regulated cell death pathways, including non-lytic (apoptosis) and innate immune lytic (pyroptosis and PANoptosis) pathways. These cell death pathways are driven by specific caspases and distinguished by their unique molecular mechanisms, supramolecular complexes, and enzymatic properties. Traditionally, caspases are classified as either apoptotic (caspase-2, -3, -6, -7, -8, -9, and -10) or inflammatory (caspase-1, -4, -5, and -11). However, extensive data from the past decades have shown that apoptotic caspases can also drive lytic inflammatory cell death downstream of innate immune sensing and inflammatory responses, such as in the case of caspase-3, -6, -7, and -8. Therefore, more inclusive classification systems based on function, substrate specificity, or the presence of pro-domains have been proposed to better reflect the multifaceted roles of caspases. In this review, we categorize caspases into CARD-, DED-, and short/no pro-domain-containing groups and examine their critical functions in innate immunity and cell death, along with their structural and molecular mechanisms, including active site/exosite properties and substrates. Additionally, we highlight the emerging roles of caspases in cellular homeostasis and therapeutic targeting. Given the clinical relevance of caspases across multiple diseases, improved understanding of these proteins and their structure–function relationships is critical for developing effective treatment strategies.https://doi.org/10.1038/s41421-025-00791-3 |
| spellingShingle | Eswar Kumar Nadendla Rebecca E. Tweedell Gary Kasof Thirumala-Devi Kanneganti Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease Cell Discovery |
| title | Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease |
| title_full | Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease |
| title_fullStr | Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease |
| title_full_unstemmed | Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease |
| title_short | Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease |
| title_sort | caspases structural and molecular mechanisms and functions in cell death innate immunity and disease |
| url | https://doi.org/10.1038/s41421-025-00791-3 |
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